Ex Parte FinegoldDownload PDFPatent Trial and Appeal BoardSep 29, 201411979007 (P.T.A.B. Sep. 29, 2014) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 11/979,007 10/30/2007 Sydney M. Finegold 30452.14USC1 5473 7590 09/30/2014 Adriano & Associates Suite 203 572 East Green Street Pasadena, CA 91101 EXAMINER TONGUE, LAKIA J ART UNIT PAPER NUMBER 1645 MAIL DATE DELIVERY MODE 09/30/2014 PAPER Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte SYDNEY M. FINEGOLD1 __________ Appeal 2012-005983 Application 11/979,007 Technology Center 1600 __________ Before ULRIKE W. JENKS, CHRISTOPHER G. PAULRAJ, and ROBERT A. POLLOCK, Administrative Patent Judges. Opinion for the Board filed by Administrative Patent Judge POLLOCK. Dissenting Opinion filed by Administrative Patent Judge PAULRAJ. POLLOCK, Administrative Patent Judge. DECISION ON APPEAL Appellant appeals under 35 U.S.C. § 134(a) from the Examiner’s Final Rejection of claims 15 and 21–26 as unpatentable under 35 U.S.C. § 112, first paragraph. We have jurisdiction under 35 U.S.C. § 6(b). We reverse. 1 According to Appellant, the Real Party in Interest is The United States Department of Veterans Affairs. (App. Br. 2). Appeal 2012-005983 Application 11/979,007 2 STATEMENT OF THE CASE Appellant’s invention relates to the treatment of autism in a subset of affected children having pathogenic, neurotoxic bacteria colonizing the gastrointestinal tract. (See e.g., Spec. 2:22–30; 4:9–23; 20:11–20.) Representative independent claim 15 (formatted) reads as follows: 15. A method of treating autism associated with colonization of pathogenic bacteria in the gastrointestinal tract of a patient, said method comprising administering to the patient suffering from autism a treatment course of an effective amount of metronidazole, bacitracin, or vancomycin thereby treating autism associated with colonization of pathogenic bacteria in the gastrointestinal tract of a patient. The following grounds of rejection are before us for review: Claims 15 and 21–26 are rejected under 35 U.S.C. § 112, first paragraph as lacking enablement. FINDINGS OF FACT Bacterial infection has been linked to a number of conditions affecting the nervous system. Clostridium tetani bacteria, the causative agent of tetanus (lockjaw) in humans, release an exotoxin called tetanospasmin, which travels through neurons resulting in nervous system irregularities including constant skeletal muscle contraction. (Spec. 5:6–19.) Another condition caused by bacterial infection, D-lactic acidosis, results from changes in intestinal bacteria to acid-tolerant, aciduric flora. (Id. 21:4–8.) D-lactic acidosis presents as “a range of behavioral changes such as hostility, slurred speech, stupor, altered mental status, dizziness, asterixis, and ataxia” wherein, treatment with oral antimicrobials “result[s] in rapid cessation of neurological signs.” (Id. 21:8–11.) Appeal 2012-005983 Application 11/979,007 3 The Specification posits a “‘gut-brain’ etiologic connection” (id. 20:11–16) wherein “pathogenic proliferation of microbes in the gut can at least partially cause deleterious neurological symptoms and syndromes of many disorders, including at least some forms of Pervasive Development Disorder including both Early-Onset and Late-Onset Autism . . . .” (Id. 4:21–23). Consistent with this hypothesis, the Specification points to observational reports of children with “repeated broad-spectrum antimicrobial use (usually for chronic otitis media), followed by chronic diarrhea, then loss of language, play, and social skills, and subsequent onset of autistic symptoms.” (Id. 15:4–6.) Applicant reasons that “repeated antimicrobial use may have disrupted a protective effect of indigenous intestinal organisms and allowed colonization by one or more neurotoxin-producing species.” (Id. 15:6–8.) The Specification identifies members of the genus Clostridium, including C. tetani, C. botulinum, C. perfringens, and C. difficile, as “plausible agents of these neurological disorders, because several members of this genus are known to produce neurotoxins, they proliferate enterically during antimicrobial therapy (e.g., C. difficile), and they have been implicated in diarrheal diseases of humans and animals.” (Id. 5:7–6:7.) The Specification notes that intestinal colonization by opportunistic pathogens such as Clostridium difficile (the causative agent of pseudomembranous colitis) is greatly enhanced when the protective intestinal microbiota is disrupted by broad-spectrum antimicrobials. (20:30– 21:2.) The Specification reports that fecal flora samples from four autistic children previously treated with broad-spectrum antimicrobials, lack anereobic cocci, chiefly peptostreptococcal species, commonly found in Appeal 2012-005983 Application 11/979,007 4 adult controls. (Id. 19:1–20:9; 22:4–12.) The Specification states that “[u]se of normal adult control fecal specimens in the present study, though not ideal, is justifiable given documented similarity to pediatric stool flora.” (Id. 22:17–19.) Noting that that an uncharacterized Peptostreptococcus species inhibits clostridia in vitro and in animals, the Specification suggests that “the absence of such organisms in certain autistic children may permit growth of clostridial or other toxin-producing bacteria through loss of competitive inhibition.” (Id. 22:14–16). Thus, “appropriately targeted antimicrobial therapy might reduce autistic symptoms in these individuals.” (Id. 15:8–9.) The Specification also discloses evidence that “antibiotic therapy directed to the proliferating microbial species, results in improved neurological function through inhibition or elimination of the proliferating species.” (Id. 4: 9–11.) The Specification discloses an index case involving a 4.5 year old Caucasian male with chronic diarrhea and autism. (Id. 22:29.) The subject’s diarrhea began at approximately 17 months of age following a course of broad spectrum antimicrobials. Social development was normal until 19 months, “when there was profound behavioral and developmental deterioration, along with emergence of severe autistic features.” (Id.) The patient achieved “rapid and dramatic clinical improvement” shortly after the initiation of a 12-week therapeutic trial of oral vancomycin. (Id.) Shortly after vancomycin discontinuation, behavioral deterioration was observed and he eventually lost most of the initial gains. (Id.) The Specification further discloses the results of an open-label trial involving eleven autistic children meeting inclusion criteria including a history of antibiotic use within two months of onset of autism symptoms, and a history of persistent loose stool, with diarrhea onset before autism Appeal 2012-005983 Application 11/979,007 5 symptoms. (Id. 16:18–17:12; 14:17–21.) Patients were provided a six-week treatment with oral vancomycin, followed by four weeks of oral probiotics. (Id. 17:9–12.) The Specification reports improvements using an analog rating scale “for the group as a whole in communication (Wilcoxon Signed Ranks Z = -2.9 p = .003) and behavior (Wilcoxon Signed Ranks Z = -2.9 p = .003),” as well as additional evidence of improvement for eight of the ten children independently evaluated by a clinical psychologist. (Id. 17:16–27; 18:6–16; 14:17–26.) The results of this study were published in the peer- reviewed Journal of Child Neurology.2 The Specification notes that “[a]lthough apparent improvement was clear by several measures, unfortunately these gains did not endure.” (Id. 18:24–25.) “During telephone follow-up (conducted weekly during the probiotic therapy), most parents reported substantial behavioral deterioration within two weeks of discontinuance of vancomycin treatment,” indicating that “the probiotic therapy used as an adjunct after vancomycin treatment had no discernible beneficial or adverse effect.” (Id. 18:26–32.) In discussing the deterioration of behavioral improvements made while on therapy, the Specification suggests that the decline “is due to the offending organism being spore-forming, and hence surviving therapy to germinate after vancomycin discontinuation, as has been documented with Clostridium difficile infection.” (Id. 21:22–23.) In light of the clinical trial results, the Specification states that, “[a]lthough the protocol utilized is not suggested as useful therapy, these results indicate that study of a possible ‘gut-flora’ 2 Sandler et al., Short-Term Benefit From Oral Vancomycin Treatment of Regressive-Onset Autism, 15 J. Child Neurology, 429–434 (2000) (submitted with Appellant’s brief). Appeal 2012-005983 Application 11/979,007 6 connection warrants further investigation as it might lead to greater pathophysiologic insight and meaningful prevention and/or treatment in a subset of children with autism.” (Id. 14:23–26.) The Specification states that the use of antibiotics among children and adults for bacterial infections is “ubiquitous,” (id. 1:19) and makes clear that treating bacterial infections of the gut with antibiotics is well known. In addition to the use of oral antibiotics in the treatment of D-lactic acidosis, discussed above, the specification further teaches that for treating Clostridium overgrowth in the gut, ramoplanin is preferable to drugs such as vancomycin and metronidazole, “which have previously been used.” (Spec. 9:7–24). ANALYSIS The claims on appeal apply a known treatment against pathogenic bacteria to a sub-population of patients suffering from the colonization of pathogenic bacteria in the gastrointestinal tract. In particular, Appellant’s claims are directed to treating those patients suffering the colonization of pathogenic bacteria in the gastrointestinal tract who also suffer from autism, with known antibiotics. The Specification provides sufficient criteria to identify these patients in the general population (e.g., Spec. 16:18–34; 14:17–21 (study inclusion criteria)) and makes clear that “[t]he treatment to reduce or eliminate such pathogenic bacteria load is well known in the art.” (App. Br. 26; see also, e.g., Spec. 9:7–24 (“Ramoplanin is preferable to drugs such as vancomycin and metronidazole, which have previously been used.”).) Moreover, the Specification provides both a scientific rationale that the treatment of certain patients with metronidazole, bacitracin or vancomycin, could ameliorate autistic symptoms, as well as evidence that Appeal 2012-005983 Application 11/979,007 7 this treatment does have beneficial (albeit temporary) effects on those symptoms. The Examiner finds the Specification not enabling “for a method of treating autism associated with colonization of pathogenic bacteria in the gastrointestinal tract of a patient comprising administering to the patient suffering from autism a treatment course of an effective amount of metronidazole, bacitracin, vancomycin.” (Ans. 4-5, 9.) At the same time, the Examiner accepts that: (1) the Specification is “enabling for a method for suppressing Clostridium infection in the gastrointestinal tract of an autistic patient comprising administering to said patient an antimicrobial agent from the group consisting of metronidazole, bacitracin, or vancomycin” (Ans. 4); (2) “there was significant improvement in the symptoms of children with delayed onset autism by providing them with antibiotics directed toward common anaerobic intestinal bacteria . . . ” (Ans. 10); and (3) the “behavior improvement was related to the drugs effect on the intestinal tract flora . . . ” (id.) In light of the above, we agree with Appellant that the Examiner has not set forth a reasonable basis to question the enablement of the claimed invention. See In re Wright, 999 F.2d 1557, 1562 (Fed. Cir. 1993). In particular, the Examiner has not established that the Specification did not teach those skilled in the art how to make and use the full scope of the Appeal 2012-005983 Application 11/979,007 8 claimed invention without undue experimentation. Genentech, Inc. v. Novo Nordisk, A/S, 108 F.3d 1361, 1365 (Fed. Cir. 1997).3 We find that the Specification provides sufficient evidence of enablement with respect to treating a subpopulation of patients, those with autism and suffering from the colonization of pathogenic bacteria in the gastrointestinal tract. As this is the only question before us on appeal, we reverse. SUMMARY We reverse the rejection of claims 15 and 21–26 under 35 U.S.C. §112, first paragraph as lacking enablement. REVERSED kme 3 While cognizant of the Examiner’s finding that autism is a “complex severe mental disorder of brain function marked by problems with social contact, intelligence and language, together with ritualistic or compulsive behavior and bizarre responses to the environment,” (e.g., Ans. 7) the Examiner’s statement that autism is not “caused” by bacteria (id.) raises an issue we need not address here as the instant claims are directed to autism “associated” with the colonization of pathogenic bacteria in the patient’s gastrointestinal tract. UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte SYDNEY M. FINEGOLD __________ Appeal 2012-005983 Application 11/979,007 Technology Center 1600 __________ Before ULRIKE W. JENKS, CHRISTOPHER G. PAULRAJ, and ROBERT A. POLLOCK, Administrative Patent Judges. PAULRAJ, Administrative Patent Judge, dissenting. I respectfully dissent from the Majority’s decision to reverse the lack of enablement rejection because the Specification does not provide sufficient guidance for a skilled artisan to practice the full scope of the claimed treatment method without undue experimentation. The Majority’s analysis begins with the premise that “Appellant’s claims are directed to treating those patients suffering the colonization of pathogenic bacteria in the gastrointestinal tract who also suffer from autism, with known antibiotics.” (Ante at 6) The plain language of Appellant’s claims, however, requires “treating autism associated with colonization of pathogenic bacteria in the gastrointestinal tract of a patient” (Cl. 15 (emphasis added)), and not merely treating bacterial infection in a subset of autistic patients, by administering an effective amount of metronidazole, Appeal 2012-005983 Application 11/979,007 2 bacitracin, or vancomycin. Consistent with the Specification (see Findings of Fact, ante at 2–6), I would interpret the claims to require the actual treatment of autistic behavior using any of those three antibiotics. In order for a medical treatment claim to satisfy the enablement requirement of Section 112, one of ordinary skill in the art must be able to effectively use the claimed treatment method in order to achieve the desired therapeutic result. See, e.g., In re ’318 Patent Infringement Litig., 583 F.3d 1317, 1325-27 (Fed. Cir. 2009); Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 1322-25 (Fed. Cir. 2005). When the claims are directed to a treatment using a particular drug, “[w]hat is necessary to satisfy the how-to- use requirement of § 112 is the disclosure of some activity coupled with knowledge as to the use of this activity.” In re Cortright, 165 F.3d 1353, 1360 (Fed. Cir. 1999) (citation omitted). Appellant’s claims do not satisfy that standard because the Specification does not establish that all three recited antibiotics can be used to effectively treat autism. It is insufficient, in my view, to simply identify patients who happen to suffer from both autism and pathogenic bacterial infection and reasonably expect to be able to treat autism by administering those known antibiotics. At the outset, it is important to recognize both the level of predictability and the state of the art concerning the treatment of autism as of the effective filing date. Appellant’s Specification acknowledges that autism is a “largely untreatable disorder” and that “no underlying etiology can be identified in the vast number of cases” (Spec. 14 l. 27–32). As found by the Examiner, “[t]he use of antibiotics for the treatment of autism is not well known nor is it an art recognized and accepted function of said antibiotics” (Ans. 6). This is undisputed by Appellant and consistent with the Appeal 2012-005983 Application 11/979,007 3 Specification’s indication that “the hypothesis that autism (in a defined subset of children) may be a sequela to the colonization of the intestinal tract by one or more neurotoxin-producing bacteria is novel . . . . ” (Spec. 20 ll. 17–20 (emphasis added)). Thus, although Appellant proposed a theory that “an alteration in colonic flora contributes to autism” based on “a possible ‘gut-brain etiological connection” (id. at 20 ll. 15–16 (emphasis added)), it was nonetheless still an unproven theory by the time the priority applications were filed in 2000 and 2001. A specification that “does no more than state a hypothesis and propose testing to determine the accuracy of that hypothesis . . . is not sufficient.” ’318 Patent Infringement Litig., 583 F.3d at 1327; see also Rasmusson, 413 F.3d at 1325 (“If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to ‘inventions’ consisting of little more than respectable guesses as to the likelihood of their success. . . . That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis.”); Cortright, 165 F.3d at 1360 (affirming lack of enablement rejection where statements in specification that applicant “believed” or “surmise[d]” that claimed activity would restore hair growth “reflect no actual observations”). To support the enablement of the claims, Appellant relies upon Example 1 in the Specification, which describes a study in which eleven autistic children with a history of antimicrobial use and persistent loose stool/chronic diarrhea were administered a regimen of vancomycin for several weeks, and videotaped for 30 minutes at baseline and once during therapy for observation by a clinical child psychologist (Spec. 14–22). Appeal 2012-005983 Application 11/979,007 4 However, as noted by the Examiner, the study does not identify any control group to which the observational results were compared (Ans. 16). For example, the study does not make any comparison to a second group of similarly situated autistic children that were administered a placebo for the same period; nor does the study make a comparison to children without autism that were administered vancomycin for the same period. Appellant responds that “the children themselves served as their own control on the effect of oral vancomycin on their autistic condition” (App. Br. 30). But a comparison to the same children’s own behavior prior to the treatment does not necessarily indicate that the observed results reflect the treatment of autism by the administered antibiotic rather than some other cause and/or effect. The Examiner therefore had good reason to question the results presented. In re Jolles, 628 F.2d 1322, 1327 (CCPA 1980) (“When utility as a drug, medicant, and the like in human therapy is alleged, it is proper for the examiner to ask for substantiating evidence unless one with ordinary skill in the art would accept the allegations as obviously correct.”). Moreover, even if the results described in the study were reliable, they only showed a temporary (short-term) improvement in autistic behavior (Spec. 18 ll. 25–28). Appellant admits based on the subsequent deterioration in behavior that “[t]he protocol utilized is not suggested as useful therapy” (Spec. 14 ll. 23–24 (emphasis added)). Furthermore, even assuming that Example 1 provides an enabling disclosure for treating autism using the particular protocol disclosed, I do not believe the full scope of the claimed invention is enabled by that single example. In re Vaeck, 947 F.2d 488, 495 (Fed. Cir. 1991) (“the first paragraph of § 112 requires that the scope of the claims must bear a Appeal 2012-005983 Application 11/979,007 5 reasonable correlation to the scope of enablement provided by the specification”). Example 1 only describes the effect of administering a single antibiotic, vancomycin, on children with “delayed-onset” (“regressive” or “late onset”) autism, whereas the claims more broadly encompass administering any one of three antibiotics—metronidazole, bacitracin, or vancomycin—to treat either early-onset or delayed-onset autism (see Cls. 22, 23). The Specification notes that early-onset autism is “clinically distinct” from delayed-onset autism, and further surmises that “[c]onventional theories are that there are genetic underpinnings to early onset autism, but it is more likely in at least some cases there is a gastrointestinal component” (Spec. 14 ll. 11–14). The Specification, however, does not provide any evidence that early-onset autism can be treated in the same manner as delayed-onset autism using antibiotics.1 There is also no evidence of record that metronidazole and bacitracin have a sufficient structural similarity with vancomycin, or otherwise would be expected to work in the same manner as vancomycin to treat either form of autism. See In re Buting, 418 F.2d 540, 544 (CCPA 1969) (finding evidence limited to one compound and two types of cancer was not “commensurate with the broad scope of utility asserted and claimed, viz. that of treating seven types of cancer with several compounds”); cf. Jolles, 628 F.2d at 1327–28 (structural relationship to known chemotherapy drugs was sufficient to establish utility for claimed composition and method for treatment of acute myeloblastic leukemia). 1 Indeed, the Specification does not even present a coherent theory in this regard as it also indicates that “[t]he invention includes a method of preventing or treating a gastrointestinal or neurological disorder other than delayed-onset autism in a patient . . . .” (Spec. 2 ll. 3–5 (emphasis added)). Appeal 2012-005983 Application 11/979,007 6 For the foregoing reasons, I would affirm the lack of enablement rejection under 35 U.S.C. 112, ¶ 1. Copy with citationCopy as parenthetical citation